Cuypers Anne, Truong Anh-Co Khanh, Becker Lisa M, Saavedra-García Paula, Carmeliet Peter
Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), Vlaams Instituut voor Biotechnologie (VIB) and Department of Oncology, Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium.
Laboratory of Angiogenesis and Vascular Heterogeneity, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Front Oncol. 2022 Aug 31;12:965277. doi: 10.3389/fonc.2022.965277. eCollection 2022.
Tumor vessel co-option (VCO) is a non-angiogenic vascularization mechanism that is a possible cause of resistance to anti-angiogenic therapy (AAT). Multiple tumors are hypothesized to primarily rely on growth factor signaling-induced sprouting angiogenesis, which is often inhibited during AAT. During VCO however, tumors invade healthy tissues by hijacking pre-existing blood vessels of the host organ to secure their blood and nutrient supply. Although VCO has been described in the context of AAT resistance, the molecular mechanisms underlying this process and the profile and characteristics of co-opted vascular cell types (endothelial cells (ECs) and pericytes) remain poorly understood, resulting in the lack of therapeutic strategies to inhibit VCO (and to overcome AAT resistance). In the past few years, novel next-generation technologies (such as single-cell RNA sequencing) have emerged and revolutionized the way of analyzing and understanding cancer biology. While most studies utilizing single-cell RNA sequencing with focus on cancer vascularization have centered around ECs during sprouting angiogenesis, we propose that this and other novel technologies can be used in future investigations to shed light on tumor EC biology during VCO. In this review, we summarize the molecular mechanisms driving VCO known to date and introduce the models used to study this phenomenon to date. We highlight VCO studies that recently emerged using sequencing approaches and propose how these and other novel state-of-the-art methods can be used in the future to further explore ECs and other cell types in the VCO process and to identify potential vulnerabilities in tumors relying on VCO. A better understanding of VCO by using novel approaches could provide new answers to the many open questions, and thus pave the way to develop new strategies to control and target tumor vascularization.
肿瘤血管共选（VCO）是一种非血管生成性血管化机制，可能是抗血管生成治疗（AAT）耐药的原因。多种肿瘤被认为主要依赖生长因子信号诱导的芽生血管生成，而这一过程在AAT期间常受到抑制。然而，在VCO过程中，肿瘤通过劫持宿主器官预先存在的血管侵入健康组织，以确保其血液和营养供应。尽管VCO已在AAT耐药的背景下被描述，但这一过程的分子机制以及被共选的血管细胞类型（内皮细胞（ECs）和周细胞）的特征仍知之甚少，导致缺乏抑制VCO（以及克服AAT耐药）的治疗策略。在过去几年中，新型的下一代技术（如单细胞RNA测序）出现并彻底改变了分析和理解癌症生物学的方式。虽然大多数利用单细胞RNA测序聚焦于癌症血管生成的研究都围绕芽生血管生成过程中的ECs展开，但我们认为，这种技术和其他新技术可用于未来的研究，以阐明VCO过程中的肿瘤EC生物学。在本综述中，我们总结了迄今为止已知的驱动VCO的分子机制，并介绍了迄今为止用于研究这一现象的模型。我们重点介绍了最近使用测序方法进行的VCO研究，并提出如何在未来使用这些以及其他新型的先进方法，进一步探索VCO过程中的ECs和其他细胞类型，并识别依赖VCO的肿瘤中的潜在弱点。通过使用新方法更好地理解VCO，可能为许多悬而未决的问题提供新的答案，从而为开发控制和靶向肿瘤血管生成的新策略铺平道路。
